Telomere length in different tissues of elderly patients

Abstract

Telomeres are supposed to play a role in cellular aging and might contribute to the genetic background of human aging and longevity. During the past few years telomere length has been measured in various human tissues. However, very little is known about the individual telomere loss in different tissues from the same donor. Therefore we have measured telomere restriction fragment (TRF) length in three unrelated tissues (leukocytes, skin and synovial tissue) of nine elderly patients (age range 73–95 years old). Dependent on the tissue specific proliferation rate we have found significantly shorter telomeres (6546 ± 519 bp, mean ± S.D.) in leukocytes compared to skin (7792 ± 596 bp, P < 0.01) and synovial tissue (7910 ± 420 bp, P < 0.001). In general, we have observed an inverse relationship between donor age and TRF length which becomes significant in leukocytes (P = 0.04, R² = 0.49) and skin specimens (P = 0.006, R² = 0.81). Interestingly, linear correlations (P values between 0.017 and 0.038, R² values between 0.54 and 0.79) were also obtained on comparison of telomere length in each pair of two different tissues from the same donor without taking donor age into account. This suggests that genetic determination of the regulation of telomere length is tissue-independent. Furthermore, our results indicate that TRF measurement in easily accessible tissues such as blood could serve as a surrogate parameter for the relative telomere length in other tissues.

Introduction

The proportion of elderly people in relation to the total world population is continuously increasing. Therefore, there is increased interest in understanding processes which might contribute to the complex mechanism of aging as well as to the pathogenesis of age-related diseases (Greengross et al., 1997, Winker, 1997).

During the past few years several types of evidence suggest that telomeres, the non-coding nucleoprotein structures at the ends of eukaryotic chromosomes, play a causal role in cellular aging and might be at least one component of the “mitotic clocks” (Reddel, 1998). The “clock mechanism” of telomeres is due to the inability of DNA polymerase to complete replication of linear chromosomal ends resulting in a continuous loss of some of the repetitive telomeric sequences which are (TTAGGG)_n in all vertebrates (Blackburn, 1991). It has been proposed that senescence occurs, at least in part, when the mean telomere length has reached a critical lower limit. Therefore, cell immortalization requires an effective mechanism for counteracting the process of continuous telomere attrition (Campisi, 1997).

The ribonucleoprotein telomerase has been found as the most prevalent mechanism which seems to be critical for the initiation and maintenance of the immortal phenotype (Greider and Blackburn, 1985, Greider and Blackburn, 1989). In agreement with the “telomere hypothesis of cell aging and immortalization” telomerase is not expressed in most postnatal somatic cells and an inverse correlation between population doublings and telomere length has been found in in vitro experiments (Allsopp et al., 1992, Chang and Harley, 1995). Since population doublings are not directly measurable in vivo donor age has been used as an indirect parameter for replicative history. Whereas, on the other hand, with increasing donor age shorter telomeres have been found for various tissues, on the other, a high interindividual variability of the TRF length for one specific age, and even at birth, has been observed (Allsopp et al., 1992, Hastie et al., 1990, Vaziri et al., 1994). Recently, these differences in mean telomere length have been shown to be, to a large extent, genetically determined (Slagboom et al., 1994). Moreover, when we accept the role of telomeres as a “mitotic clock” the observed variations of TRF length among subjects of the same age might reflect, at least in part, the known differences between chronological and biological age.

Telomere length could provide a good candidate marker of biological age since in addition to the strong association with the replicative history of cells a clear correlation between telomere length and replicative capacity has been found in vitro (Allsopp et al., 1992). Likewise, a three times higher rate of telomere loss has been found in lymphocytes of patients with trisomy 21, a genetic defect associated with premature immunosenescence (Vaziri et al., 1993). This indicates that telomere length plays a major role for further replicative potential not only in vitro but also in vivo. In addition, distinctly shorter telomeres were found in connection with sites of higher hemodynamic stress in vascular tissues which might contribute to the pathogenesis of atherosclerosis (Chang and Harley, 1995). These observations suggest that telomere length could predict the functional status of tissues more reliably than chronological age and might be useful in diagnosis of age-related diseases which are associated with a restricted replicative capacity.

Because of the wide interindividual variability of telomere length it is difficult to define a general borderline between a physiological and a pathophysiological increased telomere attrition and therefore an internal control would be helpful. So far little is known about individual telomere length regulation in different tissues. It remains to be proven whether measurement of TRF length in easily accessible specimens such as blood could serve as a surrogate parameter for other tissues.

We analyzed TRF in three tissues of different proliferation rates (peripheral blood leukocytes, skin and synovial tissue) from elderly patients in order to determine whether a tissue-specific regulation of telomere length exists.